Vol 29, No 6 (2022)
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Impact of heart failure on the clinical profile and outcomes in patients with atrial fibrillation treated with rivaroxaban. Data from the EMIR study

Manuel Anguita Sánchez1, Francisco Marín2, Jaime Masjuan3, Juan Cosín-Sales4, José Manuel Vázquez Rodríguez5, Vivencio Barrios6, Gonzalo Barón-Esquivias78, Iñaki Lekuona9, Alejandro I. Pérez-Cabeza10, Román Freixa-Pamias11, Francisco Javier Parra Jimenez12, Mohamed Monzer Khanji Khatib13, Carles Rafols Priu14, Marcelo Sanmartín Fernández15
Pubmed: 36200548
Cardiol J 2022;29(6):936-947.

Abstract

Background: The aim of this study was to analyze the impact of the presence of heart failure (HF) on the clinical profile and outcomes in patients with atrial fibrillation (AF) anticoagulated with rivaroxaban.
Methods: Observational and non-interventional study that included AF adults recruited from 79 Spanish centers, anticoagulated with rivaroxaban ≥ 6 months before inclusion. Data were analyzed according to baseline HF status.
Results: Out of 1,433 patients, 326 (22.7%) had HF at baseline. Compared to patients without HF, HF patients were older (75.3 ± 9.9 vs. 73.8 ± 9.6 years; p = 0.01), had more diabetes (36.5% vs. 24.3%; p < 0.01), coronary artery disease (28.2% vs. 12.9%; p < 0.01), renal insufficiency (31.7% vs. 22.6%; p = 0.01), higher CHA2DS2-VASc (4.5 ± 1.6 vs. 3.2 ± 1.4; p < 0.01) and HAS-BLED (1.8 ± 1.1 vs. 1.5 ± 1.0; p < 0.01). After a median follow-up of 2.5 years, among HF patients, annual rates of stroke/systemic embolism/transient ischemic attack, major adverse cardiovascular events (MACE) (non-fatal myocardial infarction, revascularization and cardiovascular death), cardiovascular death, and major bleeding were 1.2%, 3.0%, 2.0%, and 1.4%, respectively. Compared to those patients without HF, HF patients had greater annual rates of MACE (3.0% vs. 0.5%; p < 0.01) and cardiovascular death (2.0% vs. 0.2%; p < 0.01), without significant differences regarding other outcomes, including thromboembolic or bleeding events. Previous HF was an independent predictor of MACE (odds ratio 3.4; 95% confidence interval 1.6–7.3; p = 0.002) but not for thromboembolic events or major bleeding.
Conclusions: Among AF patients anticoagulated with rivaroxaban, HF patients had a worse clinical profile and a higher MACE risk and cardiovascular mortality. HF was independently associated with the development of MACE, but not with thromboembolic events or major bleeding.

clinicAL CARDIOLOGY

Original Article

Cardiology Journal

2022, Vol. 29, No. 6, 936–947

DOI: 10.5603/CJ.a2022.0091

Copyright © 2022 Via Medica

ISSN 1897–5593

eISSN 1898–018X

Impact of heart failure on the clinical profile and outcomes in patients with atrial fibrillation treated with rivaroxaban. Data from the EMIR study

Manuel Anguita Sánchez1Francisco Marín2Jaime Masjuan3Juan Cosín-Sales4José Manuel Vázquez Rodríguez5Vivencio Barrios6Gonzalo Barón-Esquivias78Iñaki Lekuona9Alejandro I. Pérez-Cabeza10Román Freixa-Pamias11Francisco Javier Parra Jimenez12Mohamed Monzer Khanji Khatib13Carles Rafols Priu14Marcelo Sanmartín Fernández15
1Department of Cardiology, Hospital Reina Sofía Córdoba, IMIBIC, University of Cordoba, Spain
2Department of Cardiology, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, University of Murcia, CIBERCV, Murcia, Spain
3Servicio de Neurología, Hospital Universitario Ramón y Cajal, IRYCIS, Departamento de Medicina, Universidad de Alcalá. Red INVICTUS, Madrid, Spain
4Department of Cardiology, Hospital Arnau de Vilanova, Valencia, Spain
5Department of Cardiology, Complejo Hospitalario Universitario A Coruña, INIBIC, CIBERCV, A Coruña, Spain
6Department of Cardiology, University Hospital Ramón y Cajal, Madrid, Alcalá University, Madrid, Spain
7Department of Cardiology, Hospital Universitario Virgen del Rocio, Universidad de Sevilla, Sevilla, Spain
8Unidad Cardiovascular, Instituto de Biotecnología de Sevilla, Centro de Investigación en Red Cardiovascular, Madrid, Spain
9Hospital Galdakao-Usansolo, Bizkaia, Spain
10Department of Cardiology, Hospital Virgen de la Victoria, CIBERCV, Málaga, Spain
11Department of Cardiology, Hospital Moisés Broggi, Barcelona, Spain
12Department of Cardiology, Centro Integral de Enfermedades Cardiovasculares, HM Hospitales, Madrid, Spain
13Department of Cardiology, Clínica LAMAR, Tomelloso (Ciudad Real), Spain
14Department of Medical Affairs, Bayer Hispania, Barcelona, Spain
15Department of Cardiology, Hospital Universitario Ramon y Cajal, Madrid, Spain

Address for correspondence: Dr. Manuel Anguita Sánchez, Department of Cardiology, Hospital Reina Sofía Córdoba, IMIBIC, University of Cordoba, 14004 Córdoba, Spain, tel: 0034 957 01 00 00, e-mail: manuelanguita@secardiologia.es

Received: 20.05.2022 Accepted: 4.09.2022 Early publication date: 4.10.2022

This article is available in open access under Creative Common Attribution-Non-Commercial-No Derivatives 4.0 International (CC BY-NC-ND 4.0) license, allowing to download articles and share them with others as long as they credit the authors and the publisher, but without permission to change them in any way or use them commercially.

Abstract
Background: The aim of this study was to analyze the impact of the presence of heart failure (HF) on the clinical profile and outcomes in patients with atrial fibrillation (AF) anticoagulated with rivaroxaban.
Methods: Observational and non-interventional study that included AF adults recruited from 79 Spanish centers, anticoagulated with rivaroxaban ≥ 6 months before inclusion. Data were analyzed according to baseline HF status.
Results: Out of 1,433 patients, 326 (22.7%) had HF at baseline. Compared to patients without HF, HF patients were older (75.3 ± 9.9 vs. 73.8 ± 9.6 years; p = 0.01), had more diabetes (36.5% vs. 24.3%; p < 0.01), coronary artery disease (28.2% vs. 12.9%; p < 0.01), renal insufficiency (31.7% vs. 22.6%; p = 0.01), higher CHA2DS2-VASc (4.5 ± 1.6 vs. 3.2 ± 1.4; p < 0.01) and HAS-BLED (1.8 ± 1.1 vs. 1.5 ± 1.0; p < 0.01). After a median follow-up of 2.5 years, among HF patients, annual rates of stroke/ /systemic embolism/transient ischemic attack, major adverse cardiovascular events (MACE) (non-fatal myocardial infarction, revascularization and cardiovascular death), cardiovascular death, and major bleeding were 1.2%, 3.0%, 2.0%, and 1.4%, respectively. Compared to those patients without HF, HF patients had greater annual rates of MACE (3.0% vs. 0.5%; p < 0.01) and cardiovascular death (2.0% vs. 0.2%; p < 0.01), without significant differences regarding other outcomes, including thromboembolic or bleeding events. Previous HF was an independent predictor of MACE (odds ratio 3.4; 95% confidence interval 1.6–7.3; p = 0.002) but not for thromboembolic events or major bleeding.
Conclusions: Among AF patients anticoagulated with rivaroxaban, HF patients had a worse clinical profile and a higher MACE risk and cardiovascular mortality. HF was independently associated with the development of MACE, but not with thromboembolic events or major bleeding. (Cardiol J 2022; 29, 6: 936–947)
Key words: atrial fibrillation, bleeding, EMIR, heart failure, MACE, rivaroxaban, stroke

Introduction

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in adults worldwide, and it is expected to increase, mainly due to the extended longevity in the overall population as well as the increasing burden of other comorbidities such as hypertension, diabetes, or heart failure (HF) [1–3]. Despite anticoagulation markedly decreasing the risk of stroke, patients remain at risk of cardiovascular disease, including coronary artery disease, HF and cardiovascular death [4, 5].

Heart failure and AF are two common conditions that frequently coexist. In fact, the presence of one entity may precipitate/exacerbate the other [5–7]. Remarkably, the increased risk of AF occurs in both, HF with reduced left ventricular ejection fraction (LVEF) (HFrEF) and HF with preserved LVEF (HFpEF) [8]. This is not surprising, as AF and HF share common risk factors and comorbidities. In addition, dilatation of left atrium, left atrial and ventricular fibrosis, chronic inflammation, neurohormonal hyperactivation, and electrophysiologic remodeling also play a relevant role [9, 10]. The concomitance of both conditions translates into higher morbidity and mortality rates, including a greater risk of thromboembolic events, and consequently, anticoagulation is recommended [6, 11–13]. Although a number of studies have analyzed the impact of HF on patients with AF taking vitamin K antagonists, the information currently available among patients treated with direct oral anticoagulants, particularly in clinical practice remains scarce [14–18].

In ROCKET-AF, rivaroxaban was noninferior to warfarin for the prevention of stroke and systemic embolic events and significantly reduced intracranial hemorrhage in patients with AF at high thromboembolic risk [19]. In a specific analysis of the ROCKET-AF trial, the relative efficacy and safety of rivaroxaban versus warfarin was independent of HF status [20]. However, data about the role of rivaroxaban among patients with HF and AF in clinical practice are warranted [21].

The EMIR (Estudio observacional para la identificación de los factores de riesgo asociados a eventos cardiovasculares mayores en pacientes con fibrilación auricular no valvular tratados con un anticoagulante oral directo [Rivaroxaban] [“Observational study to identify risk factors associated with major cardiovascular events in patients with nonvalvular atrial fibrillation treated with a direct oral anticoagulant [rivaroxaban]”) study [22, 23] was aimed to evaluate the performance of the cardiovascular risk 2MACE score in AF patients treated with rivaroxaban. In this study, the impact of the presence of HF at baseline on the clinical profile and outcomes in AF patients anticoagulated with rivaroxaban was analyzed.

Methods

The design and methods of the EMIR study have been extensively described in previous publications [22, 23]. Briefly, EMIR was a non-interventional and observational study that included patients 18 years or older, with an established diagnosis of AF (either paroxysmal, persistent or permanent), anticoagulated with rivaroxaban according to clinical practice ≥ 6 months before being enrolled and they provided written informed consent. Patients were recruited from 79 Spanish centers (hospitals and private clinics). By contrast, patients with prosthetic heart valves, any severe valvopathy, severe cognitive impairment, chronic infections or systemic autoimmune diseases, active cancer or severe liver insufficiency were excluded from the study. The study was approved by each participating Institutional Review Board.

Patients were followed-up during 2.5 years with 4 visits (baseline, 12 months, 24 months, and study end) that should coincide with any of the patients’ routine visits for HF management. No additional visits, laboratory tests, other diagnostic tests or treatments were specifically performed or prescribed for being included in the EMIR study. All data were recorded using an electronic case report form specifically created for the EMIR study.

At baseline, biodemographic data (age, sex, permanent AF, body mass index), risk stratification (CHA2DS2-VASc, HAS-BLED, and 2MACE score), cardiovascular risk factors (hypertension, diabetes), vascular disease (previous coronary artery disease, prior cerebrovascular disease, peripheral artery disease) and renal insufficiency were recorded. Data were collected from the clinical history of the patients and during the interview with the patient during the patients’ routine visit. The presence of HF was considered when it was reflected in the clinical history of the patient. Data were analyzed according to the presence of previous HF and the HF subtypes. HFrEF was defined as HF with a LVEF < 40%, HF with mildly reduced LVEF (HFmrEF) as HF with LVEF 40 – < 50% and HFpEF as HF with LVEF ≥ 50%. Renal insufficiency was defined as an estimated glomerular filtration rate < 60 mL/min/1.73 m2 by the MDRD-4 formula.

Events (major adverse cardiovascular events [MACE], thromboembolic events, myocardial infarction [MI], revascularization, cardiovascular death, death from any cause and major bleeding) during the study were evaluated. MACE events were defined as a combination of non-fatal MI, revascularization and cardiovascular death (death for coronary events, progressive HF death and sudden cardiac death). Thromboembolic events included stroke, systemic embolism and transient ischemic attack. Major bleedings were defined following the International Society of Thrombosis and Hemostasis definition [24]. The information source was in all cases the medical record and the patient. The investigator collected the study data from medical records or from personal interviews performed during the study follow-up. Before the present study started at the sites, all investigators were sufficiently trained on the background and objectives of the study. All outcome variables and covariates were recorded in a standardized electronic case report form. Medical review of the data was performed according to the medical review plan. A scientific committee independently evaluated and classified the events. Events were analyzed according to HF status and the HF subtypes. In addition, predictors of MACE, ischemic stroke and major bleeding in the EMIR population were analyzed.

Statement of ethics

This study protocol was reviewed and approved firstly by CAEIG (Comité Autonómico de Etica de Galicia) on July 14th, 2016, approval number 2016/348.

Patients were recruited from 79 Spanish centers (hospitals and private clinics). The study was approved by each participating Institutional Review Board.

Patients provided written informed consent.

Statistical methods

Qualitative variables were presented as absolute and relative frequencies and quantitative variables were described with measures of central tendency (mean and median) and dispersion (standard deviation and interquartile range). Qualitative variables were compared using the c2 test or the Fisher exact test, as required. When 2 means were compared, the t test or the Mann-Whitney test was used, when appropriate and 3 means (HF subtypes) by the Kruskal-Wallis test. Annual event rates were calculated. To assess predictors of MACE, thromboembolic events and major bleeding (dependent variables), multivariate analyzes were performed. The multivariate models began to be constructed by introducing those factors with a significance of p < 0.15 in the bivariates by the automatic variable selection method by steps forward and backward. Only the significant factors (p < 0.05) were finally considered to build the model. Odd ratios (OR) along with the 95% confidence interval (CI) were calculated. The following independent variables were considered: age (continuous variable), sex (female vs. male), body mass index (continuous variable), previous bleeding, diabetes, permanent AF, ischemic heart disease, coronary revascularization, antiplatelet agents, previous cerebrovascular disease, dependence level (dependent vs. autonomous), hypertension, hyperlipidemia, smoking, pulmonary disease, renal insufficiency, liver dysfunction, cancer, peripheral artery disease, alcohol use, non-severe dementia, HF, CHA2DS2-VASc (continuous variable), HAS-BLED (continuous variable) and 2MACE ≥ 3. A level of statistical significance of 0.05 was applied in all the statistical tests. The data were analyzed using the statistical package SPSS (v18.0 or superior).

Results

A total of 1,503 patients were initially enrolled. After the exclusion of 70 patients, 1,433 (93.7%) patients from 79 Spanish centers, were included for the final analysis, of whom 326 (22.7%) had HF at baseline (Fig. 1).

Figure 1. Flow chart of the study population.

The baseline clinical characteristics of the overall study population and according to HF status are presented in Table 1A. Overall, mean age was 74.2 ± 9.7 years, 55.5% of patients were men, 37.5% had permanent AF, mean CHA2DS2-VASc score was 3.5 ± 1.5, mean HAS-BLED was 1.6 ± 1.0 and 26.9% had a 2MACE score ≥ 3. In addition, 79.3% of patients had hypertension, 27.1% diabetes, 28.3% vascular disease, 24.7% renal insufficiency (defined by MDRD-4 < 60 mL/ /min/1.73 m2), 16.4% ischemic heart disease and 12.5% prior cerebrovascular disease.

Among patients with HF (n = 326), 94 had HFrEF, 59 HFmrEF and 173 HFpEF. In patients with HF, mean LVEF was 48.0 ± 14.3%. Baseline clinical characteristics were analyzed according to HF status (Table 1A). Compared to patients without HF, patients with HF were older (75.3 ± 9.9 vs. 73.8 ± 9.6 years; p = 0.01), had more diabetes (36.5% vs. 24.3%; p < 0.01), permanent AF (50.9% vs. 33.3%; p < 0.01), previous coronary artery disease (28.2% vs. 12.9%; p < 0.01), renal insufficiency (MDRD-4: 31.7% vs. 22.6%; p = 0.001), as well as higher CHA2DS2-VASc score (4.5 ± 1.6 vs. 3.2 ± 1.4; p < 0.01), HAS-BLED score (1.8 ± ± 1.1 vs. 1.5 ± 1.0; p < 0.01) and more patients had a 2MACE score ≥ 3 (46.0% vs. 21.2%; p < 0.01). With regard to the baseline clinical characteristics according to HF subtype, patients with HFpEF were older, more commonly women, had a higher CHA2DS2-VASc score and more hypertension. By contrast, patients with HFrEF were more commonly men, had a higher 2MACE score ≥ 3 and more previous MI (Table 1B).

Table 1A. Clinical characteristics of the study population at baseline according to heart failure (HF) status.

Total population (n = 1,433; 100%)

HF population (n = 326; 22.7%)

No HF population (n = 1,107;77.3%)

P

Biodemographic data

Age [years]

74.2 ± 9.7

75.3 ± 9.9

73.8 ± 9.6

0.01

≥ 75 years

691 (48.2%)

173 (53.1%)

518 (46.8%)

0.05

Sex (men)

795 (55.5%)

193 (59.2%)

602 (54.4%)

0.12

Permanent atrial fibrillation

535 (37.5%)

166 (50.9%)

369 (33.3%)

< 0.01

Body mass index [kg/m2]

29.1 ± 4.9

29.8 ± 5.3

28.9 ± 4.8

0.03

Risk stratification

CHA2DS2-VASc score

3.5 ± 1.5

4.5 ± 1.6

3.2 ± 1.4

< 0.01

2MACE score ≥ 3

385 (26.9%)

150 (46.0%)

235 (21.2%)

< 0.01

HAS-BLED score

1.6 ± 1.0

1.8 ± 1.1

1.5 ± 1.0

< 0.01

Cardiovascular risk factors

Hypertension

1,137 (79.3%)

261 (80.1%)

876 (79.1%)

0.72

Diabetes

388 (27.1%)

119 (36.5%)

269 (24.3%)

< 0.01

Vascular disease

Vascular disease

406 (28.3%)

127 (39.0%)

279 (25.2%)

< 0.01

Previous coronary disease

235 (16.4%)

92 (28.2%)

143 (12.9%)

< 0.01

Prior cerebrovascular disease

179 (12.5%)

42 (12.9%)

137(12.4%)

0.81

Peripheral artery disease and/or aortic plaque

96 (6.7%)

33 (10.1%)

63 (5.7%)

0.005

Peripheral artery disease

58 (4.0%)

22 (6.7%)

36 (3.3%)

0.005

Other conditions/comorbidities

Renal insufficiency (MDRD-4: < 60 mL/min/1.73 m2)

350 (24.7%)

103 (31.7%)

247 (22.6%)

0.01

Renal insufficiency (Cockcroft-Gault: < 60 mL/min/1.73 m2)

498 (35.1%)

133 (40.8%)

365 (33.0%)

0.01

Table 1B. Clinical characteristics of the study population at baseline according to heart failure (HF) subtype.

HFpEF

HFmrEF

HFrEF

P

Biodemographic data

N

173

59

94

Proportion in the overall population

12.1%

4.1%

6.6%

Proportion in the HF population

53.1%

18.1%

28.8%

Age [years]

77.5 ± 9.3

73.3 ± 9.8

72.6 ± 10.2

< 0.001

≥ 75 years

111 (64.2%)

23 (39.0%)

39 (41.5%)

< 0.001

Sex (men)

79 (45.7%)

42 (71.2%)

72 (76.6%)

< 0.001

Permanent atrial fibrillation

79 (45.7%)

30 (50.8%)

51 (54.3%)

0.39

Body mass index [kg/m2]

30.6 ± 5.5

29.0 ± 5.3

28.8 ± 4.7

0.016

Risk stratification

CHA2DS2-VASc score

4.9 ± 1.4

4.0 ± 1.5

4.2 ± 1.8

< 0.001

2MACE score ≥ 3

71 (41.0%)

21 (35.6%)

58 (61.7%)

0.001

HAS-BLED score

1.9±1.0

1.7±1.1

1.6±1.2

0.15

Cardiovascular risk factors

Arterial hypertension

149 (86.1%)

45 (76.3%)

67 (71.3%)

0.011

Diabetes

65 (37.6%)

21 (35.6%)

33 (35.1%)

0.91

Vascular disease

Vascular disease

59 (34.1%)

24 (40.7%)

44 (46.8%)

0.12

Previous coronary disease

39 (22.5%)

20 (33.9%)

33 (35.1%)

0.053

Previous myocardial infarction

12 (6.9%)

10 (16.9%)

25 (26.6%)

< 0.001

Previous cerebrovascular disease

23 (13.3%)

5 (8.5%)

14 (14.9%)

0.50

Peripheral artery disease and/or aortic plaque

17 (9.8%)

8 (13.6%)

8 (8.5%)

0.59

Peripheral artery disease

9 (5.2%)

7 (11.9%)

6 (6.4%)

0.21

Other conditions/comorbidities

Renal insufficiency (MDRD-4: < 60 mL/min/1.73 m2)

51 (29.5%)

19 (32.2%)

33 (35.5%)

0.60

Renal insufficiency (Cockcroft-Gault: < 60 mL/min/1.73 m2)

70 (40.5%)

24 (40.7%)

39 (41.9%)

0.97

The mean follow-up was 2.2 ± 0.6 years (median 2.5 years, interquartile range 2.2–2.6 years). The annual rates of relevant events were calculated over 1,425 patients (323 out of 326 patients with HF and 1,102 out of 1,107 patients without HF) (Table 2A). Overall, 87 (6.1%) patients died during the study period, of whom 20 (1.4%) had a cardiovascular origin, where 13 (0.9%) were due to progressive chronic HF. As a result, 70.0% of cardiovascular deaths were caused by progressive HF. Among patients with baseline HF, annual rates of (stroke + systemic embolism + transient ischemic attack), MACE, cardiovascular death, death from any cause and major bleeding were 1.2%, 3.0%, 2.0%, 5.5% and 1.4%, respectively. Compared to those patients without HF at baseline, those patients with HF had greater annual rates of MACE (3.0% vs. 0.5%; p < 0.01), cardiovascular death (2.0% vs. 0.2%; p < 0.01) and death from any cause (5.5% vs. 2.0%; p < 0.01), without significant differences regarding other outcomes, including thromboembolic or bleeding events. With regard to events during the follow-up according to HF subtype, patients with HFpEF had more thromboembolic events and patients with HFrEF more MACE, MI and cardiovascular death (Table 2B).

Table 2A. Events during the follow-up according to heart failure (HF) status.

Total

HF (n = 326)

No HF (n = 1,107)

P

Stroke + SE + TIA:

Number patients (%)

23 (1.6)

8 (2.5)

15 (1.4)

0.17

Annual rate events (%)*

0.7

1.2

0.6

0.22

Major bleeding:

Number patients (%)

29 (2.0)

8 (2.5)

21 (1.9)

0.53

Annual rate events (%)*

1.0

1.4

0.9

0.33

MACE:

Number patients (%)

30 (2.1)

17 (5.2)

13 (1.2)

< 0.01

Annual rate events (%)*

1.1

3.0

0.5

< 0.01

Myocardial infarction:

Number patients (%)

5 (0.3)

3 (0.9)

2 (0.2)

0.08

Annual rate events (%)*

0.2

0.4

0.1

0.15

Revascularization:

Number patients (%)

9 (0.6)

4 (1.2)

5 (0.5)

0.13

Annual rate events (%)*

0.3

0.6

0.2

0.22

Cardiovascular death:

Number patients (%)

20 (1.4)

13 (4.0)

7 (0.6)

< 0.01

Annual rate events (%)*

0.6

2.0

0.2

< 0.01

Death from any cause:

Number patients (%)

87 (6.1)

38 (11.7)

49 (4.4)

< 0.01

Annual rate events (%)*

2.7

5.5

2.0

< 0.01

Table 2B. Events during the follow-up according to heart failure subtype.

Type of heart failure

P

HFpEF (n = 173)

Annual rate of events (n = 171; accumulated time = 386.81 years)

HFmrEF (n = 59)

Annual rate of events (n = 58; accumulated time = 128.29 years)

HFrEF (n = 94)

Annual rate of events (n = 94; accumulated time = 179.80 years)

Stroke + SE + TIA:

Number patients (%)

8 (4.6)

0

0

0.036

Annual rate events (%)*

2.07

0

0

HFpEF vs. HFrEF: p < 0.05

Major bleeding:

Number patients (%)

6 (3.5)

0

2 (2.1)

0.392

Annual rate events (%)*

1.81

0

1.67

No statistically significant difference

MACE:

< 0.001

Number patients (%)

2 (1.2)

1 (1.7)

14 (14.9)

HFpEF vs. HFrEF: p < 0.001

Annual rate events (%)*

0.78

0.78

9.45

HFmrEF vs. HFrEF: p < 0.001

Myocardial infarction:

Number patients (%)

0

0

3 (3.2)

0.029

Annual rate events (%)*

0

0

1.67

HFpEF vs. HFrEF: p < 0.05

Revascularization:

Number patients (%)

1 (0.6)

0

3 (3.2)

0.110

Annual rate events (%)*

0.26

0

1.67

No statistically significant difference

Cardiovascular death:

< 0.001

Number patients (%)

2 (1.2)

1 (1.7)

11 (11.7)

HFpEF vs. HFrEF: p < 0.001

Annual rate events (%)*

0.52

0.78

6.12

HFmrEF vs. HFrEF: p < 0.05

Death from any cause:

Number patients (%)

14 (8.1)

6 (10.2)

18 (19.1)

0.025

Annual rate events (%)*

3.62

4.68

10.01

HFpEF vs. HFrEF: p < 0.05

A multivariate logistic regression analysis was performed to study the potential predictors of MACE events, thromboembolic events and major bleeding (Table 3). The presence of ischemic heart disease, renal insufficiency and HF were independent predictive factors associated to MACE in the global population. Type of AF did not have an impact on MACE risk (p = 0.662). On the other hand, the use of antiplatelet agents, non-severe dementia and CHA2DS2-VASc score were independently associated with the development of thromboembolic events and a score 2MACE ≥ 3, dependency and HAS-BLED score with major bleeding. The main results of the study are presented in Figure 2.

Table 3. Predictors of MACE, ischemic stroke and major bleeding in the EMIR population.

Independent variables

Univariate analyzis

Multivariate analyzis

P

OR

95% CI

P

OR

95% CI

Dependent variable “MACE events”

Antiplatelet agents

< 0.01

13.6

6.3–29.6

Heart failure

< 0.01

4.7

2.2–10.1

0.002

3.4

1.6–7.3

Coronary revascularization

< 0.01

4.6

2.1–10.1

Ischemic heart disease

< 0.01

4.6

2.2–9.8

0.002

3.4

1.6–7.3

2MACE ≥ 3

0.002

3.2

1.5–6.9

Renal insufficiency

0.007

3.0

1.4–6.5

0.02

2.5

1.2–5.5

Peripheral artery disease

0.08

2.9

0.9–10.1

Diabetes

0.15

1.8

0.8–3.8

HAS-BLED (continuous variable)

0.02

1.5

1.1–2.1

CHA2DS2-VASC (continuous variable)

0.05

1.3

1.0–1.6

Sex (female vs. male)

0.02

0.3

0.1–0.8

Dependent variable “Thromboembolic events”

Antiplatelet agents

< 0.01

9.2

3.7–22.7

< 0.01

9.0

3.5–23.0

Non-severe dementia

0.002

7.7

2.2–27.5

0.02

5.5

1.3–22.7

2MACE ≥ 3

< 0.01

4.5

1.9–11.1

Heart failure

0.002

3.8

1.6–9.1

Previous bleeding

0.12

3.3

0.7–14.5

Diabetes

0.01

3.0

1.3–7.2

Previous stroke

0.03

2.8

1.1–7.4

Coronary revascularization

0.04

2.8

1.1–7.3

Ischemic heart disease

0.04

2.6

1.0–6.5

CHA2DS2-VASc (continuous variable)

0.002

1.5

1.2–1.9

0.01

1.4

1.1–1.8

Age (continuous variable)

0.15

1.0

1.0–1.1

Dependent variable “Major bleeding”

Arterial hypertension

0.049

7.5

1.0–55.0

Non-severe dementia

0.009

5.3

1.5–18.4

Previous bleeding

0.003

5.2

1.7–15.6

Patient autonomy (dependent vs. autonomous)

< 0.01

4.7

2.1–10.7

0.03

2.6

1.1–6.1

2MACE ≥ 3

< 0.01

4.6

2.2–9.9

0.02

2.6

1.1–6.1

Renal insufficiency

< 0.01

4.4

2.1–9.3

Previous stroke

0.004

3.2

1.4–7.2

Antiplatelet agents

0.03

3.0

1.1–8.0

HAS-BLED (continuous variable)

< 0.01

2.2

1.6–3.0

0.01

1.9

1.3–2.7

Coronary revascularization

0.07

2.2

0.9–5.3

Diabetes

0.08

1.9

0.9–4.1

Hyperlipidemia

0.14

1.8

0.8–4.1

CHA2DS2-VASc (continuous variable)

< 0.01

1.6

1.3–2.0

Age (continuous variable)

< 0.01

1.1

1.0–1.1

Figure 2. Graphical abstract; AF — atrial fibrillation; CI — confidence interval; HF — heart failure; MACE — major adverse cardiovascular events; OR — odds ratio; SE — systemic embolism; TIA — transient ischemic attack.

Discussion

The present study showed that in a wide sample of real-life patients with AF anticoagulated with rivaroxaban compared to those patients without HF at baseline, individuals with previous HF have a worse clinical profile and a higher risk of MACE (cardiac mortality, coronary revascularization, non-fatal MI) and cardiovascular mortality. In addition, the history of HF is independently associated with the development of MACE, but not with stroke or major bleeding. Despite that, rates of MACE and death remained low in HF patients, indicating that anticoagulation with rivaroxaban may be a good choice in this population. This information is relevant, as although previous studies have analyzed the impact of HF on outcomes in anticoagulated AF patients, very scarce information is available in those patients taken rivaroxaban [21].

In the EMIR study, nearly 23% of AF patients presented with HF at baseline. This is in line with previous studies performed in Spain that have shown that the concomitance of both conditions is very common in clinical practice. Thus, in the PAULA study, that included AF patients treated in a primary care setting and anticoagulated with vitamin K antagonists, approximately 24% of patients had HF [25]. More recently, in the FANTASIIA study that included AF patients in a specialized cardiology setting and anticoagulated with direct oral anticoagulants or vitamin K antagonists, nearly 30% of patients also had HF [26]. In the international GLORIA-AF registry, in which AF patients anticoagulated with a direct oral anticoagulant were enrolled, 24% of patients had HF at baseline [27]. Conversely, different studies have shown that approximately one third of patients with HF also have AF [28, 29]. As each entity enhances the development of the other one [5, 6], an active search should be promoted to rule out the concomitance of both conditions [1].

In the current study, more patients had HFpEF than HFrEF or HFmrEF. Although some authors have not shown significant differences in the strength of an association between AF and the type of HF [8], other authors have reported that among HF patients, AF is progressively more common with increasing LVEF [28, 30, 31]. Despite previous studies showing that HFpEF accounts for at least half of the cases of HF, it is very likely that due to the ageing of the population, this proportion will increase in the following years, as well as the number of patients with AF and HF concomitantly [32, 33]. Remarkably, the present study showed that there were relevant differences in the clinical profile of patients according to HF subtype, particularly related with age, sex and some comorbidities. These differences are in line with previous studies of HF population [34, 35].

Compared to patients without HF, patients with HF had a worse clinical profile, with more risk factors, and comorbidities, as well as a greater thromboembolic and bleeding risk. This high-risk profile in patients with HF has also been observed in previous studies [29]. As a result, to reduce the disease burden in this population, all patients with HF and AF should receive in addition to anticoagulation, guideline-adherent HF therapy [36].

Remarkably, different studies have shown that the superiority of direct oral anticoagulants over vitamin K antagonists remain in patients with HF, in both, clinical trials and real-life studies [16–18]. In addition, it is more difficult to attain an adequate time in therapeutic range among patients taking vitamin K antagonists in patients with HF, leading to a lower protection [15]. In the current study, all patients were taking rivaroxaban. After a median follow-up of 2.5 years, among patients with previous HF, annual rates of thromboembolic events, cardiovascular death, death from any cause and major bleeding were 1.2%, 2.0%, 5.5%, and 1.4%, respectively. In the rivaroxaban arm of the ROCKET-AF trial, these numbers were 1.9%, 3.4%, 5.1%, and 14.2% for major or nonmajor clinically relevant bleeding, respectively [20]. A retrospective study performed in the United States that analyzed patients with HF and AF taking rivaroxaban between 2011 and 2016 showed that after a median follow-up of 1.4 years, rates of stroke or systemic embolism, ischemic stroke, major bleeding and intracranial hemorrhage were 1.0, 0.7, 3.9, and 0.3 events per 100 person-years, respectively [21]. As a result, in clinical practice, rates of outcomes in patients with HF and AF seem lower than those reported in the ROCKET-AF trial [20].

Although in non-anticoagulated patients the most devastating consequence related to AF is stroke and its associated complications (death and disability), anticoagulation changes mortality and outcome patterns in AF patients. Thus, in the anticoagulated AF population, most deaths are cardiac-related (cardiovascular death, MI and HF), and only a small proportion are associated with stroke and bleeding [37]. This has also been described in the AF population with HF, including those patients with HF enrolled in the ROCKET-AF trial [18, 20, 38]. Likewise, in the present study, compared to those patients without HF at baseline, those patients with HF had greater annual rates of MACE and cardiovascular death, but with similar rates of thromboembolic and bleeding events. In addition, the multivariate analyzes showed that previous HF was independently associated with the development of MACE, but not with thromboembolic events or major bleeding. Therefore, anticoagulation is not only important in AF patients with HF, but also choosing an oral anticoagulant that effectively reduces MACE events [1]. In this context, experimental and clinical studies have shown that rivaroxaban decreases the progression of ischemic cardiomyopathy, as well as the risk of MI and cardiovascular death [39–42]. Of note, the use of antiplatelet agents was independently associated with the development of thromboembolic events. In the AFIRE trial, rivaroxaban monotherapy was noninferior to a combination of rivaroxaban with an antiplatelet agent for thromboembolic events or death, and superior for major bleeding in AF patients with stable coronary artery disease, and this occurred irrespective of their risk for stroke and bleeding [43]. Therefore, all these data indicate that rivaroxaban in monotherapy should be considered in patients with HF and AF, not only to reduce the risk of thromboembolic events, but also the risk of MACE and cardiovascular mortality, leading to a comprehensive management of this population. On the other hand, despite the AMADEUS study, which showed that the risk of cardiovascular death, stroke, or systemic embolism increased among patients with permanent AF (vs. nonpermanent AF), regardless the presence of HF [44], in the present study the type of AF was not associated with an increased risk of outcomes. However, it should be noted that idraparinux and vitamin K antagonists were the anticoagulants used in AMADEUS, compared with rivaroxaban in the study herein. On the other hand, the current study showed that the risk of events varied according to HF subtype (thromboembolic events in HFpEF and MACE, MI and cardiovascular death in HFrEF). Other studies have also shown differences in outcomes according to HF subtype [45]. As a result, these particularities should be taken into account to provide a comprehensive approach in the management of patients with AF and HF.

Limitations of the study

As this was an observational study, no control group was available, and the presence of some confounding factors could not be excluded. However, the high number of patients included, as well as that the recruitment was performed consecutively after office consultation, may reduce possible selection bias. On the other hand, it should be considered that the patients were recruited after at least 6 months under rivaroxaban treatment. Therefore, the results of this study can only be extended to a similar population.

Conclusions

Nearly 1 out of 4 patients with AF anticoagulated with rivaroxaban in clinical practice have HF concomitantly. After a median follow-up of 2.5 years, annual rates of thromboembolic events, MACE, cardiovascular death, and major bleeding in HF population are 1.2%, 3.0%, 2.0%, and 1.4%, respectively. Compared to patients without HF, HF patients are older, have a greater baseline risk profile, and a higher risk of developing MACE and cardiovascular mortality, but not thromboembolic or bleeding events. The management of patients with HF and AF requires a comprehensive approach, with the aim to reduce not only the stroke risk, but also cardiovascular-related complications. In this context, rivaroxaban should be considered as a first-line therapy in the treatment of patients with HF and AF in clinical practice.

Acknowledgments

Writing and editorial assistance was provided by Content Ed Net (Madrid, Spain) with funding from Bayer Hispania.

Funding

The EMIR Study was funded by Bayer Hispania SL.

Conflict of interest: Manuel Anguita Sánchez has received funding for consulting and conference services from Bayer, Daiichi-Sankyo and Pfizer; Francisco Marín has received consultancy/lecturing fees from Bayer, Boehringer Ingelheim, Pfizer, Bristol Myers Squibb, Daiichi Sankyo and AFNET; Jaime Masjuan has received consultancy/lecturing fees from Bayer, Boehringer Ingelheim, Pfizer, Bristol Myers Squibb y Daiichi Sankyo; Juan Cosín-Sales has received consultancy/lecture fees from Bayer, BMS/Pfizer, Boehringer Ingelheim, and Daiichi Sankyo; José Manuel Vázquez Rodríguez has received lecturing fees from Bayer, Pfizer and Daiichi Sankyo; Vivencio Barrios has received consultancy/ /lecture fees from Bayer, BMS/Pfizer, Boehringer Ingelheim, and Daiichi Sankyo; Gonzalo Barón-Esquivias has received honoraria as advisor from Bayer, Daiichi-Sankyo, BMS-Pfizer and Rovi; and honoraria as speaker from Boehringer-Ingelheim, Bayer, Daiichi-Sankyo, BMS and Pfizer; Iñaki Lekuona has received honoraria for presentations from Bayer, Boehringer Ingelheim, Daiichi Sankyo, and Pfizer-BMS; Alejandro I. Pérez-Cabeza has received personal fees for educational activities or participation in boards from Daiichi Sankyo, Bayer, Boehringer Ingelheim and Bristol Myers Squibb; Román Freixa-Pamias has received honoraria for presentations from Bayer, Boehringer Ingelheim, Daiichi Sankyo, and Pfizer-BMS; Francisco Javier Parra Jimenez has received financial compensation from Bayer for participating in the EMIR study; Mohamed Monzer Khanji Khatib has received financial compensation from Bayer for participating in the EMIR study; Carles Rafols Priu is an employee Bayer Hispania SL; Marcelo Sanmartín Fernández has received speaker and advisory fees from the following companies in the past 3 years: Bayer, Boehringer Ingelheim, BMS and Pfizer.

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